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Characterization of natural product inhibitors of quorum sensing reveals competitive inhibition of Pseudomonas aeruginosa RhlR by ortho -vanillin.

التفاصيل البيبلوغرافية
العنوان: Characterization of natural product inhibitors of quorum sensing reveals competitive inhibition of Pseudomonas aeruginosa RhlR by ortho -vanillin.
المؤلفون: Woods KE; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Akhter S; Center for Computational Biology, University of Kansas, Lawrence, Kansas, USA., Rodriguez B; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Townsend KA; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Smith N; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Smith B; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Wambua A; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Craddock V; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Abisado-Duque RG; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Santa EE; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Manson DE; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Oakley BR; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Hancock LE; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA., Miao Y; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA.; Center for Computational Biology, University of Kansas, Lawrence, Kansas, USA., Blackwell HE; Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA., Chandler JR; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas, USA.
المصدر: Microbiology spectrum [Microbiol Spectr] 2024 Sep 03; Vol. 12 (9), pp. e0068124. Date of Electronic Publication: 2024 Jul 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: ASM Press Country of Publication: United States NLM ID: 101634614 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2165-0497 (Electronic) Linking ISSN: 21650497 NLM ISO Abbreviation: Microbiol Spectr Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : ASM Press, 2013-
مواضيع طبية MeSH: Quorum Sensing*/drug effects , Pseudomonas aeruginosa*/drug effects , Pseudomonas aeruginosa*/metabolism , Pseudomonas aeruginosa*/physiology , Pseudomonas aeruginosa*/genetics , Bacterial Proteins*/metabolism , Bacterial Proteins*/antagonists & inhibitors , Bacterial Proteins*/genetics , Benzaldehydes*/pharmacology , Benzaldehydes*/chemistry , Biological Products*/pharmacology , Biological Products*/chemistry , Trans-Activators*/metabolism , Trans-Activators*/antagonists & inhibitors , Trans-Activators*/genetics , Anti-Bacterial Agents*/pharmacology
مستخلص: Quorum sensing (QS) is a cell-cell signaling system that enables bacteria to coordinate population density-dependent changes in behavior. This chemical communication pathway is mediated by diffusible N -acyl L-homoserine lactone signals and cytoplasmic signal-responsive LuxR-type receptors in Gram-negative bacteria. As many common pathogenic bacteria use QS to regulate virulence, there is significant interest in disrupting QS as a potential therapeutic strategy. Prior studies have implicated the natural products salicylic acid, cinnamaldehyde, and other related benzaldehyde derivatives as inhibitors of QS in the opportunistic pathogen Pseudomonas aeruginosa, yet we lack an understanding of the mechanisms by which these compounds function. Herein, we evaluate the activity of a set of benzaldehyde derivatives using heterologous reporters of the P. aeruginosa LasR and RhlR QS signal receptors. We find that most tested benzaldehyde derivatives can antagonize LasR or RhlR reporter activation at micromolar concentrations, although certain molecules also cause mild growth defects and nonspecific reporter antagonism. Notably, several compounds showed promising RhlR or LasR-specific inhibitory activities over a range of concentrations below that causing toxicity. ortho -Vanillin, a previously untested compound, was the most promising within this set. Competition experiments against the native ligands for LasR and RhlR revealed that ortho -vanillin can interact competitively with RhlR but not with LasR. Overall, these studies expand our understanding of benzaldehyde activities in the LasR and RhlR receptors and reveal potentially promising effects of ortho -vanillin as a small molecule QS modulator against RhlR.
Importance: Quorum sensing (QS) regulates many aspects of bacterial pathogenesis and has attracted much interest as a target for anti-virulence therapies over the past 30 years, for example, antagonists of the LasR and RhlR QS receptors in Pseudomonas aeruginosa . Potent and selective QS inhibitors remain relatively scarce. However, natural products have provided a bounty of chemical scaffolds with anti-QS activities, but their molecular mechanisms are poorly characterized. The current study serves to fill this void by examining the activity of an important and wide-spread class of natural product QS modulators, benzaldehydes, and related derivatives, in LasR and RhlR. We demonstrate that ortho -vanillin can act as a competitive inhibitor of RhlR, a receptor that has emerged and may supplant LasR in certain settings as a target for P. aeruginosa QS control. The results and insights provided herein will advance the design of chemical tools to study QS with improved activities and selectivities.
Competing Interests: The authors declare no conflict of interest.
التعليقات: Update of: bioRxiv. 2024 Mar 13:2024.02.24.581676. doi: 10.1101/2024.02.24.581676. (PMID: 38559250)
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معلومات مُعتمدة: R35GM133572 United States NH NIH HHS; R35 GM131817 United States GM NIGMS NIH HHS; T34GM136453 HHS | National Institutes of Health (NIH); P20 GM103418 United States GM NIGMS NIH HHS; 15160174 Fulbright U.S. Student Program
فهرسة مساهمة: Keywords: LasR; Pseudomonas aeruginosa; RhlR; anti-virulence; inhibitor; quorum sensing; vanillin
المشرفين على المادة: 0 (Bacterial Proteins)
0 (Benzaldehydes)
0 (Biological Products)
0 (Trans-Activators)
0 (Anti-Bacterial Agents)
CHI530446X (vanillin)
0 (RhlR protein, Pseudomonas aeruginosa)
0 (LasR protein, Pseudomonas aeruginosa)
تواريخ الأحداث: Date Created: 20240724 Date Completed: 20240903 Latest Revision: 20240904
رمز التحديث: 20240904
DOI: 10.1128/spectrum.00681-24
PMID: 39046261
قاعدة البيانات: MEDLINE
الوصف
تدمد:2165-0497
DOI:10.1128/spectrum.00681-24